Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

PKP4 and Sick Sinus Syndrome

PKP4 (plakophilin‑4) has been implicated as a potential genetic modifier in sick sinus syndrome. In a recent multi‐patient exome sequencing study of a multigenerational family with sinus node dysfunction, ventricular arrhythmia, cardiomyopathy, congestive heart failure, and sudden death (PMID:27182706), PKP4 was identified among several candidate modifier genes in the presence of a primary LMNA splice‑site mutation. The study reported a family history of more than 10 affected individuals (PMID:27182706), highlighting a modest segregation signal for additional modifiers including PKP4.

Although no specific PKP4 coding variant meeting HGVS criteria was reported in the context of sick sinus syndrome, the identification of rare or novel PKP4 variants alongside other candidate modifiers supports a potential contributory role via a haploinsufficiency mechanism. Functional evidence directly linking PKP4 dysfunction to cardiac conduction defects in sick sinus syndrome is lacking, and further targeted functional assays are needed to confirm its role. Overall, while the current genetic and experimental evidence is limited, the reported observations suggest that PKP4 may serve as a useful modifier in diagnostic assessments of sick sinus syndrome.

References

  • PloS one • 2016 • Exome Sequencing Identifies a Novel LMNA Splice-Site Mutation and Multigenic Heterozygosity of Potential Modifiers in a Family with Sick Sinus Syndrome, Dilated Cardiomyopathy, and Sudden Cardiac Death PMID:27182706

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Evidence from a multi‐patient study indicates PKP4 as a potential modifier in sick sinus syndrome in a family with >10 affected individuals (PMID:27182706); however, direct causative variants and robust segregation data are lacking.

Genetic Evidence

Limited

PKP4 variants have only been observed in the context of multigenic heterozygosity without a clearly defined, pathogenic coding change, limiting the available genetic evidence (PMID:27182706).

Functional Evidence

Limited

While PKP4 is known to play roles in cell–cell adhesion and tissue organization, no functional assays directly linking its dysfunction to the cardiac conduction defects observed in sick sinus syndrome have been reported.